Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is characterized by neuronal cell loss and the deposition of protein aggregates. These neuropathological parameters are correlated with the presence of numerous markers of oxidative stress in the cell bodies of neurons suggesting the involvement of oxidative mechanisms in neuronal cell loss and/or protein deposition. Although the sources of the reactive oxygen species (ROS) leading to this oxidative stress have not been clarified, the brain responds to this chronic oxidative challenge by upregulating antioxidant defense systems (eg. increasing SOD1 and glutathione peroxidase expression). We now have three lines of evidence indicating that the increased generation of Abeta in AD also may be a compensatory response to oxidative stress that prevents neuronal apoptosis. Firstly, we have determined from in vitro studies that Abeta has significant antioxidant (superoxide dismutase) activity, secondly, that nanomolar concentrations of Abeta block apoptosis of neurons following trophic factor withdrawal, and thirdly that the Abeta amyloid burden of the AD-affected brain is significantly negatively correlated with oxidative stress markers. In support of these findings, we find fewer oxidative modifications in amyloid deposits and neurofibrillary tangles compared with the cell bodies of the neurons of AD-affected brains. Together, these compelling data provide a plausible physiological explanation for the increased generation of Abeta in AD and following head trauma. We hypothesize that as the disease progresses, the chronic overproduction of hydrogen peroxide by neuronal cells, microglia and Abeta amyloid deposits may overwhelm the antioxidant defense systems of the aging brain with the end result that ROS promote the apoptotic demise. Thus, the novel aspect of our hypothesis is the recognition that Abeta generation may be a form of pleiotrophic antagonism, whereby Abeta may be physiologically purposive under "normal" conditions (i.e. moderately increased concentrations of superoxide and/or high reducing equivalents), but may promote neuronal cell death under abnormal conditions (i.e. high concentrations of superoxide and Abeta that lead to excess hydrogen peroxide/low reducing equivalents). The proposed studies will therefore examine the generation of Abeta as a compensatory mechanism to oxidative stress that is both antioxidant and anti-apoptotic in nature while testing whether overwhelming oxidative challenges promote apoptosis. We also will test whether oxidative stress induces neurons to re-enter the cell cycle as a mechanism leading to cell death.